Design, synthesis, in vitro, and in vivo anticancer and antiangiogenic activity of novel 3-arylaminobenzofuran derivatives targeting the colchicine site on tubulin

Romagnoli, Romeo, Baraldi, Pier Giovanni, Salvador, Maria Kimatrai, Prencipe, Filippo, Lopez-Cara, Carlota, Schiaffino Ortega, Santiago, Brancale, Andrea ORCID: https://orcid.org/0000-0002-9728-3419, Hamel, Ernest, Castagliuolo, Ignazio, Mitola, Stefania, Ronca, Roberto, Bortolozzi, Roberta, Porcù, Elena, Basso, Giuseppe and Viola, Giampietro 2015. Design, synthesis, in vitro, and in vivo anticancer and antiangiogenic activity of novel 3-arylaminobenzofuran derivatives targeting the colchicine site on tubulin. Journal of Medicinal Chemistry 58 (7) , pp. 3209-3222. 10.1021/acs.jmedchem.5b00155

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Abstract

A new series of compounds characterized by the presence of a 2-methoxy/ethoxycarbonyl group, combined with either no substituent or a methoxy group at each of the four possible positions of the benzene portion of the 3-(3′,4′,5′-trimethoxyanilino)benzo[b]furan skeleton, were evaluated for antiproliferative activity against cancer cells in culture and, for selected, highly active compounds, inhibition of tubulin polymerization, cell cycle effects, and in vivo potency. The greatest antiproliferative activity occurred with a methoxy group introduced at the C-6 position, the least with this substituent at C-4. Thus far, the most promising compound in this series was 2-methoxycarbonyl-3-(3′,4′,5′-trimethoxyanilino)-6-methoxybenzo[b]furan (3g), which inhibited cancer cell growth at nanomolar concentrations (IC50 values of 0.3–27 nM), bound to the colchicine site of tubulin, induced apoptosis, and showed, both in vitro and in vivo, potent vascular disrupting properties derived from the effect of this compound on vascular endothelial cells. Compound 3g had in vivo antitumor activity in a murine model comparable to the activity obtained with combretastatin A-4 phosphate.

Item Type:	Article
Date Type:	Publication
Schools:	Pharmacy
Subjects:	R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) R Medicine > RM Therapeutics. Pharmacology
Publisher:	American Chemical Society
ISSN:	0022-2623
Date of First Compliant Deposit:	30 March 2016
Date of Acceptance:	28 January 2015
Last Modified:	05 Jan 2024 16:51
URI:	https://orca.cardiff.ac.uk/id/eprint/75334

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